The development of asthma requires exposure to inciting agents such as allergens and environmental pollutants, as well as the presence of host or genetic factors. Understanding the genetics of bronchial hyperresponsiveness (BHR) and allergy will delineate mechanisms that are important in the pathogenesis and therapy of asthma. While both genetic and environmental factors and their interactions are felt to be important, their precise role is not fully understood. A unique opportunity exists to investigate the genetics of asthma by reexamining a carefully characterized population of patients with asthma, and by studying their families. The probands are from the "asthma" center Beatrixoord in Haren, The Netherlands which was started in 1962. In collaboration with our Dutch co-investigator, Dr Dirkje Postma, data are available on approximately 1200 patients who were first studied in 1963-1970 using the same protocol. Family studies of the children and grandchildren of these original probands are underway. At this time, 85 complete families have been characterized and clinical data and DNA are available for analysis in Baltimore. Families are being ascertained so that we will be able to test the fit of genetic models through segregation analyses. The major aim of this proposal is identify major genes for bronchial hyperresponsiveness (BHR) and asthma by linkage with highly polymorphic DNA markers. Since allergy is commonly associated with asthma, a second goal of this proposal is to identify major genes for atopy using similar linkage studies. Allergic factors including skin test reactivity to common allergens, serum total and specific IgE levels, and blood eosinophilia will be studied. Complex segregation analysis will be performed separately for asthma, BHR and allergy. The most parsimonious model from the segregation analysis will be used for linkage analysis. Initially, candidate regions of the genome will be evaluated. Then, a systematic search of the genome will be performed using highly polymorphic informative makers. When a linkage is detected, candidate genes in that specific area will be studied.